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Renal function and venous thromboembolic diseases
Journal des Maladies Vasculaires (2016) 41, 389—395
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REVIEW
Renal function and venous thromboembolic diseases Fonction rénale et maladies tromboemboliques veineuses N. Janus a,b,∗, I. Mahé c, V. Launay-Vacher a,b, J.-P. Laroche d, G. Deray a,b a
Service ICAR, Pitié-Salpêtrière university hospital, 83, boulevard de l’Hôpital, 75013 Paris, France Department of nephrology, Pitié-Salpêtrière hospital, 75013 Paris, France c Internal medicine department, Louis-Mourier hospital, 92701 Colombes, France d Vascular medicine department, Saint-Eloi hospital, 34000 Montpellier, France b
Received 18 March 2016; accepted 18 September 2016 Available online 28 October 2016
KEYWORDS Venous thromboembolism; Chronic kidney disease; Anticoagulants agents
MOTS CLÉS Anticoagulants ; Maladie thrombo-embolique veineuse ; Insuffisance rénale chronique ∗
Summary Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary. © 2016 Elsevier Masson SAS. All rights reserved.
Résumé Les anticoagulants ont été approuvés par les autorités européennes dans l’indication de traitement et de prévention des maladies thromboemboliques veineuses (MTEV). Cependant, l’insuffisance rénale chronique (IRC) est : (1) fréquente chez les patients présentant une MTEV ; et (2) étroitement liée à l’apparition des MTEV. Ainsi, il existe un nombre croissant de patients présentant une IRC et une MTEV et de plus en plus de médecins et de pharmaciens sont confrontés à la question de la gestion des anticoagulants chez ces patients à cause des modifications de la pharmacocinétique des anticoagulants. Ces modifications peuvent conduire à des surdosages
Corresponding author. Service ICAR, Pitié-Salpêtrière university hospital, 83, boulevard de l’Hôpital, 75013 Paris, France. E-mail address: [email protected] (N. Janus).
http://dx.doi.org/10.1016/j.jmv.2016.09.001 0398-0499/© 2016 Elsevier Masson SAS. All rights reserved.
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N. Janus et al. et des effets indésirables dose-dépendants, comme des hémorragies. Il est donc nécessaire de dépister l’IRC chez ces patients et d’adapter la posologie des anticoagulants au besoin. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Chronic kidney disease: a silent deadly threat Chronic kidney disease (CKD) is a frequent pathology. In the United States, the National Health And Nutrition Examination Survey (NHANES) study, conducted between 1999 and 2004, reported that more than 13% of subjects presented a stage 1 to 4 CKD according to the classification of the Kidney Disease Improving Global Outcomes/Kidney Disease Outcomes Quality Initiative (KDIGO/KDOQI) [1—4]. Moreover, the French study MONA-LISA reported that the prevalence of CKD, defined by a glomerular filtration rate (GFR) ranging from 60 to 15 mL/min/1,73 m2 was 8.2% in a population aged from 35 to 75 years, in the community setting [5]. Moreover, among CKD patients, 98% did not know that they were suffering from CKD. CKD is thus under-diagnosed in France. CKD patients are at risk of clot formation and several unique conditions to this population influence the risk of thrombosis [6]. The mechanisms for increased coagulation are multifactorial. These patients are known to have increased levels of procoagulant factors [7]. Simultaneously, a decrease in endogenous anticoagulants and fibrinolytic activity might occur [8]. Commonly used medications such as erythropoietin stimulating agents can also increase the risk of thromboembolism, but these medications are more used in patients with more advanced CKD or in cancer patients receiving chemotherapy inducing anemia [9—11]. Depending on the location, graft material, surgical technique, and the patients’ own coagulable state, thrombosis of vascular access can be increased. The degree of hypercoagulability can increase as renal function declines and continues to increase during concurrent anticoagulation therapy [6]. Finally, surgery and cancer are risk factors of VTE in severe CKD patients [12]. Several studies investigated a potential link between CKD and venous thromboembolism (VTE). Wiesholzer et al were the first to report a relationship between these two diseases [13]. Thereafter, several studies showed the high prevalence of CKD in VTE patients. Cook et al. reported that 22.1% of VTE patients had a creatinine clearance (CrCl) < 60 mL/min [14]. The RIETE register (Registro Informatizado de la Enfermedad TromboEmbólica) showed that this prevalence was increasing over time, with 12.3% of VTE patients having a CrCl < 60 mL/min in 2006, and 18.1% in 2013 [15,16]. Therefore, there was an increase of nearly 6% in 7 years between the two publications (a relative increase of 47% when comparing 2013 to 2006). Finally, the Worcester Venous Thromboembolism study [17] reported that 36.7% of VTE patients had a GFR < 60 mL/min/1.73 m2 when it was estimated with CKD-EPI formula [18]. Although the prevalence varied from one study to another, it is undeniable that CKD is common in VTE patients. Moreover, other studies have shown that the relationship between CKD and VTE was in ‘‘both directions’’. Indeed, the Longitudinal investigation of thromboembolism etiology (LITE) study showed that among 19,073 patients followed
for 12 years, CKD was found to be a risk factor for VTE. In this study, annual incidences of VTE increased according to the renal function: 1.9 and 4.5 per 1000 patients among stage 2, and stage 3&4 CKD patients, respectively. The relative risk (RR) (adjusted for age, sex and race of the patients) of developing VTE was 2.1 with a 95% confidence interval (95% CI) of [1.5—3.0]. Moreover, this risk appeared early in the course of CKD, appearing for a GFR below 75 mL/min/1.73 m2 (estimated with the MDRD formula) [19]. Another study confirmed that the increased risk for VTE was beginning for a relatively high value of GFR. In this study, the risk appeared when the GFR reached 88 mL/min/1.73 m2 in a pooled analysis of 5 prospective studies that included 95,154 patients [20]. Furthermore, the hazard ratio (HR) for VTE was increasing with the decrease in GFR (estimated with CKD-EPI). Compared to normal renal function patients, CKD is a major risk factor for VTE, at a relatively early stage of renal disease, which only increases as the renal functions deteriorate. In addition, CKD is a risk factor for atherothrombosis [21], cardiovascular morbidity and mortality [22] and fatal pulmonary embolism (PE) in multivariate analysis [15]. CKD is also a risk factor of symptomatic PE and major bleeding [23]. In fact, CKD patients are at an increased risk of bleeding. Platelets can become dysfunctional, secondary to uremic related toxin exposure and can have further adhesion defects as a result of shear wall stress alterations during hemodialysis [6,24,25]. Blood loss and lower hemoglobin values can be a concern for dialysis efficiency in addition to providing adequate tissue oxygenation in a population prone to anemia. This may be most critical in comorbid conditions such as asthma or coronary artery disease [6]. It is therefore necessary to diagnose CKD and to monitor the progression of renal disease in order to optimize the management of these patients and to adjust their drug dosages, when necessary.
Prescriptions and ATHIR rules Prior to prescribing anticoagulant treatments such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs), a diagnosis needs to be made, followed by an assessment of the renal function (which will also be made during the treatment). When prescribing anticoagulant agents, a biological evaluation of the feasibility of starting the therapy in daily practice is possible with the ATHIR rule [26]: • A as anemia: full blood count, because anemia is a significant bleeding risk factor; • T as thrombocytopenia: platelet count, because an unknown thrombocytopenia is a haemorrhagic risk factor
Renal function and venous thromboembolic diseases and thrombocytosis is a risk factor for thrombosis; in some cases platelet monitoring is necessary; • H as haemostasis: quick test, prothrombin time and activated partial thromboplastin time are all informative parameters on haemostasis; • IR as insuffisance rénale (renal insufficiency): GFR according to an adequate formula. ATHIR rules are more common sense rules but if all these parameters are evaluated, anticoagulation therapy could be secure. These parameters also allow to detect bleeders [27]. From July to August 2014, the French Society of Vascular Medicine conducted a survey on this issue (188 answers). Eighty-eight percent of vascular medicine doctors prescribed an initial laboratory test at the initiation of an anticoagulant therapy. Overall, the rules of prescription were followed but some improvement is still possible. From a practical point of view, the prescription of anticoagulant agents must be done with reflection, according to the recommendations/good practices and with close communication with the patient.
Renal function The assessment of renal function has two objectives: one is clinical and the other is pharmacological. The clinical objective of this assessment is to estimate the risk of bleeding and the risk of recurrence VTE in patients treated with anticoagulants agents. The evaluation of renal function is historically carried out by using the Cockcroft-Gault formula (CG) [28]. Indeed, the literature data show a correlation between the result of the CG formula and the risk of: bleeding, fatal bleeding and fatal pulmonary embolism [12,15,23]. However, several studies have reported similar or better correlations when the assessment of renal function was performed with either the MDRD formula [29] or the CKD-EPI formula [18]. The second objective (pharmacological) is to evaluate the renal function in order to adjust the doses of all drugs and of anticoagulant agents in particular. Indeed, in CKD patients, it is necessary to adjust the dosage in order to avoid drug overdose secondary to the modification of the pharmacokinetic parameters of the drug. About half of available drugs in France today require a dose reduction in patients with CKD. For the remaining 50%, the drug must be given at its usual dose, even in cases of renal failure, to avoid inefficiency. It is therefore imperative to have access to reliable sources of information in order to determine the appropriate dose according to the CKD stage. This question is global and arises in all medical specialties and diseases. It has thus been shown that poor adaptation dosages have been associated with an increased mortality of about 25% in oncology [30,31], 16% in HIV infections [32], or 40% to 6 years in the elderly general French population [33]. The international Kidney disease: improving global outcomes (KDIGO) working group defined CKD in 2005 [3] and stated how to estimate the renal function for drug dosage adjustments in 2011 [34]. In both cases, it is stated that the method for estimating renal function should be as precise as possible and that, at the moment, the most accurate formula is the CKD-EPI. One important point to know is
391 that CKD-EPI and MDRD formulae show very similar performances when the GFR is lower than 60 mL/min/1.73 m2 and it is for this cut-off of GFR that the question of drug dosage adaptation is important. It is in fact rare that a drug requires a dosage adjustment when GFR is greater than 60 mL/min/1.73 m2 . Furthermore, the CG formula is inaccurate in elderly patients and in subjects with a body mass index greater than 25 or less than 18.5 [35,36]. In addition, the method for serum creatinine dosing has evolved several times since the development of the CG formula in 1976. Currently, laboratories use the Isotope dilution mass spectrophotometry (IDMS) method, which is more accurate than the method previously used. The CG formula has never been validated with these new techniques. The CKD-EPI and the MDRD formulas have been validated with the IDMS method. In addition, drug agencies and Scientific Societies have reported that the CG formula should be abandon for the estimation of the renal function (French Biomedicine Agency and French Nephrology Society [37], International Society of Geriatric Oncology [38], French National Health Authority [39]). For all these reasons, nephrologists are using the CKD-EPI formula (or at least the MDRD formula). However, because the CG formula was used in the clinical trial of most of anticoagulant agents, vascular physicians and cardiologists are using CG.
Low molecular weight heparins Low molecular weight heparins (LMWH) are a heterogeneous group of drugs. All LMWHs are composed of heparin chains of different lengths and weights. The relative composition between short and long chains varies from one drug to another [40]. Thus, enoxaparin has more short chains, excreted by the kidney, while tinzaparin has a majority of long chains, which are not eliminated by the kidney. This point is very important because short chains (enoxaparin) are eliminated by the renal glomerular filtration while long chains (tinzaparin) adhere to the surface of endothelial cells and are degraded in situ. However, LMWH are contra-indicated in CKD patients with severe renal impairment [41], which was one of the criteria of non-inclusion in the clinical trials. Several studies have investigated about the use of LMWH in CKD patients. It has been reported that LMWH with long chains (tinzaparin) did not accumulate at the prophylactic dosage of 4500 IU/day at day 1 and 8 in CKD patients unlike shorter chain LMWH (enoxaparin) used at the prophylactic dosage of 4000 IU/day [42] (Table 1). Furthermore, no tinzaparin accumulation was reported between day 2 and 5 in moderate and severe renal impairment patients with VTE in the IRIS study [43]. For curative VTE treatment, it was suggested to reduce the dosage of enoxaparin to reduce the bleeding risk observed in severe CKD patients [44].
Unfractionated heparin No modification of the pharmacokinetic of unfractionated heparin (UFH) was reported in CKD patients. Therefore, it can be used with the usual dosage in these patients, regardless of the level of renal function [45].
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Table 1 Pharmacokinetic parameters of tinzaparin/enoxaparin in CKD patients [42]. Paramètres pharmacocinétiques de la tinzaparine et de l’enoxaparine chez les patients insuffisants rénaux chroniques [42]. Tinzaparin Cmax , IU/mL (mean ± SD) Day 1 0.44 ± 0.16 Day 8 0.46 ± 0.19 P-value (Day 1 vs 8) > 0.05 AUC, IU/mL/min (mean ± SD) Day 1 252 ± 103 Day 8 273 ± 111 P-value (Day 1 vs 8) > 0.05 Trough level, IU/mL (mean ± SD) Day 1 0.05 ± 0.04 Day 8 0.06 ± 0.06 P-value (Day 1 vs 8) > 0.05
Enoxaparin 0.55 ± 0.14 0.67 ± 0.23 < 0.001 354 ± 119 447 ± 218 < 0.001 0.06 ± 0.06 0.11 ± 0.10 0.01
SD: standard deviation.
Vitamin K antagonist Data showed that the treatment with vitamin K antagonist (VKA) in CKD patients is neither easy nor standardized. There are no specific recommendations on the dosage adjustment of these drugs in CKD patients. VKA treatment for AF in patients with severe CKD has a poor safety and efficacy profile, likely related to suboptimal anticoagulation control. Furthermore, patients with severe CKD were at a high risk of stroke or transient ischemic attack and major bleeds during VKA treatment compared to those without CKD, HR = 2.75 (95% CI = 1.25—6.05) and HR = 1.66 (95% CI = 0.97—2.86), or with moderate CKD, HR = 3.93 (95% CI = 1.71—9.00) and HR = 1.86 (95% CI = 1.08—3.21), respectively [46]. Moreover, fluindione is nephrotoxic and several publications have reported that fluindione could induce acute interstitial nephritis [47,48]. Consequently, it is hard to use VKA in CKD patients and the use of these drugs expose the patient to higher risks of bleeding.
Direct oral anticoagulants DOACs are predominantly eliminated by the kidney. The frequency of renal excretion of the DOACs ranged from 59 to 85% according to the drug [49]. Modifications of the pharmacokinetic parameters of these drugs in CKD patients have been reported for the three DOACs available in France and it is necessary to adjust their dosage in CKD patients [41,50]. Clinical trials were conducted in CKD patients but patients with creatinine clearance < 30 mL/min were excluded from these studies [51—56]. The French National Drug Agency (Agence nationale pour la sécurité des médicaments [ANSM]) published a report in 2014 on the management of anticoagulants and recommended that these drugs be used with ‘‘great caution’’ and to reduce DOACs dosage but without any precise dosage. However, some recommendations from the Summary of product characteristics (SmPC) are available but not clearly applicable.
According to the SmPC of apixaban, a dose reduction is necessary in AF patients with CG between 15 and 30 mL/min. This conclusion seems awkward because the choice of apixaban dosage was not based on CG in the clinical trials but on creatininemia, age and weight (Amplify [56]; Amplify-EXT [57]; Averroes [52] and Aristotle [51,58]). In addition, there is a contradiction between the clinical trials and the SmPC that could lead to mistakes. For example, a 78-year-old man weighing 68 kg with a Scr = 218 mol/L should have received a full dose of apixaban in the clinical trial, according to the criteria; but, according to apixaban SmPC, this patient should receive a reduced dose in real life. Therefore, it is impossible to recommend a reduced/full dose of apixaban in CKD patients because the clinical trial methodology does not match with the apixaban SmPC recommendations. Chang et al. [59] performed a single dose pharmacokinetic study of apixaban (10 mg) in CKD patients. An increase of systemic exposure (from +27% to +77%) was reported and that the frequency of adverse events in patients with various degrees of CKD ranged from 29% to 42%, and was higher than that in subjects with normal renal function (13%). There were also a high variability in serum apixaban concentrations [60]. In addition, one study reported a pharmacokinetic study of apixaban performed in hemodialysis patients. The study showed an increase in systemic exposure (+36%) of apixaban after a single 5 mg dose [61]. The authors stated that ‘‘no dose adjustment is recommended in ESRD patients for any indication, with exception of non-valvular atrial fibrillation’’ and that in these patients ‘‘with ESRD and at least one the following characteristics: age ≥ 80 years, body weight ≤ 60 kg. It is recommended that apixaban dose be reduced from 5 mg twice daily to 2.5 mg twice daily’’. From a nephrological point of view, this statement is strange because hemodialysis patients have no renal function, regardless of their age and/or weight. Therefore, it is hard to recommend a dose on the basis of this study. The clinical trial of dabigatran randomized (CKD patients did not receive a specific experimental dose) patients into 2 different dose-groups (110 or 150 mg BID) of dabigatran in normal renal function patients and in CKD patients [62]. A pharmacokinetic simulation based on the data from the clinical trial of dabigatran was performed [63]. Based on the model, the authors reported that a dose of 75 mg BID could reach the target drug plasma concentration and that the exposure of the drug could be within the concentration range proved to be safe and effective. This dosing algorithm was also confirmed and supported by the FDA clinical pharmacology division but not by the European medicine agency. Among the 3 available DOACs, only the clinical development of rivaroxaban included one clinical trial with a dedicated dosage of rivaroxaban in a specific group of CKD patients with an estimation of the renal function [53]. Furthermore, several pharmacokinetic studies performed in hemodialysis patients reported that rivaroxaban was safe and efficient in these patients [64,65]. Finally, the clinical trials of the coming DOAC (edoxaban) included CKD patients for which a specific dosage was investigated [66,67]. Several others studies were performed and confirmed that edoxaban was safe and effective in CKD patients, including hemodialysis patients [68—71]. Consequently, it is necessary to reduce the doses of DOACs in CKD patients.
Renal function and venous thromboembolic diseases
Conclusion VTE is strongly associated to CKD. The main consequence of this association is a higher mortality in VTE patients with CKD than in patient without CKD. Therefore, it is important to screen and diagnose CKD in VTE patients using at least an adequate formula for the estimation of the glomerular filtration rate. CKD is not a ‘‘modifiable’’ risk factor, however its diagnosis could allow physicians to slow down the progression of the CKD by managing, for example, the known risk factors of CKD progression (such as diabetes, hypertension, nephrotoxic drug) and therefore, reduce the risk of VTE and the risk of death since it is correlated to the DFG.
Disclosure of interest Janus N: Leo Pharma, Pfizer, Vifor Pharma, Roche, Gilead, Daïchi-Sankyo, Guerbet, Amgen, Bayer, Pierre Fabre Oncologie. Launay-Vacher V: Amgen, Leo Pharma, Merck, Pierre Fabre Oncologie, Roche, Takeda, Teva, Bayer, BoehringerIngelheim, Hospira, Helsinn, Leo Pharma, Roche, Gilead, Daïchi-Sankyo, Guerbet. Avec le soutien institutionnel de Léo Pharma.
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by fluindione must be addressed. Nephrol Dial Transplant 2012;27:1554—8. Belmouaz S, Desport E, Abou Ayache R, Thierry A, Mignot A, Bauwens M, et al. Acute immuno-allergic interstitial nephritis caused by fluindione. Clin Nephrol 2006;66:455—8. Bauersachs RM. Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups. Eur J Intern Med 2014;25:600—6. Harel Z, Sholzberg M, Shah PS, Pavenski K, Harel S, Wald R, et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol JASN 2014;25:431—42. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981—92. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806—17. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883—91. Einstein investigators, Bauersachs R, Berkowitz SD, Brenner B, Büller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: 2499—510. Einstein-PE investigators, Büller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287—97. Agnelli G, Büller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799—808. Agnelli G, Büller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699—708. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the Aristotle trial. Eur Heart J 2012;33:2821—30. Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 2016;56:637—45. Stöllberger C, Finsterer J. Pipe dreams about apixaban for stroke prevention in renal impairment. J Clin Pharmacol 2016;56:646—7. Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol 2016;56:628—36. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139—51. Lehr T, Haertter S, Liesenfeld KH, Staab A, Clemens A, Reilly PA, et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol 2012;52:1373—8. De Vriese AS, Caluwé R, Bailleul E, De Bacquer D, Borrey D, Van Vlem B, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 2015;66:91—8. Dias C, Moore KT, Murphy J, Ariyawansa J, Smith W, Mills RM, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol 2016;43:229—36. investigators Hokusai-VTE, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for
Renal function and venous thromboembolic diseases the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406—15. [67] Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093—104. [68] Fuji T, Fujita S, Kawai Y, Abe Y, Kimura T, Fukuzawa M, et al. A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery. Thromb J 2015;13:6. [69] Parasrampuria DA, Marbury T, Matsushima N, Chen S, Wickremasingha PK, He L, et al. Pharmacokinetics, safety, and
395 tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015;113: 719—27. [70] Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment. Circ J 2015;79:1486—95. [71] Jönsson S, Simonsson USH, Miller R, Karlsson MO. Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol 2015;55:1268—79.
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REVIEW
Renal function and venous thromboembolic diseases Fonction rénale et maladies tromboemboliques veineuses N. Janus a,b,∗, I. Mahé c, V. Launay-Vacher a,b, J.-P. Laroche d, G. Deray a,b a
Service ICAR, Pitié-Salpêtrière university hospital, 83, boulevard de l’Hôpital, 75013 Paris, France Department of nephrology, Pitié-Salpêtrière hospital, 75013 Paris, France c Internal medicine department, Louis-Mourier hospital, 92701 Colombes, France d Vascular medicine department, Saint-Eloi hospital, 34000 Montpellier, France b
Received 18 March 2016; accepted 18 September 2016 Available online 28 October 2016
KEYWORDS Venous thromboembolism; Chronic kidney disease; Anticoagulants agents
MOTS CLÉS Anticoagulants ; Maladie thrombo-embolique veineuse ; Insuffisance rénale chronique ∗
Summary Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary. © 2016 Elsevier Masson SAS. All rights reserved.
Résumé Les anticoagulants ont été approuvés par les autorités européennes dans l’indication de traitement et de prévention des maladies thromboemboliques veineuses (MTEV). Cependant, l’insuffisance rénale chronique (IRC) est : (1) fréquente chez les patients présentant une MTEV ; et (2) étroitement liée à l’apparition des MTEV. Ainsi, il existe un nombre croissant de patients présentant une IRC et une MTEV et de plus en plus de médecins et de pharmaciens sont confrontés à la question de la gestion des anticoagulants chez ces patients à cause des modifications de la pharmacocinétique des anticoagulants. Ces modifications peuvent conduire à des surdosages
Corresponding author. Service ICAR, Pitié-Salpêtrière university hospital, 83, boulevard de l’Hôpital, 75013 Paris, France. E-mail address: [email protected] (N. Janus).
http://dx.doi.org/10.1016/j.jmv.2016.09.001 0398-0499/© 2016 Elsevier Masson SAS. All rights reserved.
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N. Janus et al. et des effets indésirables dose-dépendants, comme des hémorragies. Il est donc nécessaire de dépister l’IRC chez ces patients et d’adapter la posologie des anticoagulants au besoin. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Chronic kidney disease: a silent deadly threat Chronic kidney disease (CKD) is a frequent pathology. In the United States, the National Health And Nutrition Examination Survey (NHANES) study, conducted between 1999 and 2004, reported that more than 13% of subjects presented a stage 1 to 4 CKD according to the classification of the Kidney Disease Improving Global Outcomes/Kidney Disease Outcomes Quality Initiative (KDIGO/KDOQI) [1—4]. Moreover, the French study MONA-LISA reported that the prevalence of CKD, defined by a glomerular filtration rate (GFR) ranging from 60 to 15 mL/min/1,73 m2 was 8.2% in a population aged from 35 to 75 years, in the community setting [5]. Moreover, among CKD patients, 98% did not know that they were suffering from CKD. CKD is thus under-diagnosed in France. CKD patients are at risk of clot formation and several unique conditions to this population influence the risk of thrombosis [6]. The mechanisms for increased coagulation are multifactorial. These patients are known to have increased levels of procoagulant factors [7]. Simultaneously, a decrease in endogenous anticoagulants and fibrinolytic activity might occur [8]. Commonly used medications such as erythropoietin stimulating agents can also increase the risk of thromboembolism, but these medications are more used in patients with more advanced CKD or in cancer patients receiving chemotherapy inducing anemia [9—11]. Depending on the location, graft material, surgical technique, and the patients’ own coagulable state, thrombosis of vascular access can be increased. The degree of hypercoagulability can increase as renal function declines and continues to increase during concurrent anticoagulation therapy [6]. Finally, surgery and cancer are risk factors of VTE in severe CKD patients [12]. Several studies investigated a potential link between CKD and venous thromboembolism (VTE). Wiesholzer et al were the first to report a relationship between these two diseases [13]. Thereafter, several studies showed the high prevalence of CKD in VTE patients. Cook et al. reported that 22.1% of VTE patients had a creatinine clearance (CrCl) < 60 mL/min [14]. The RIETE register (Registro Informatizado de la Enfermedad TromboEmbólica) showed that this prevalence was increasing over time, with 12.3% of VTE patients having a CrCl < 60 mL/min in 2006, and 18.1% in 2013 [15,16]. Therefore, there was an increase of nearly 6% in 7 years between the two publications (a relative increase of 47% when comparing 2013 to 2006). Finally, the Worcester Venous Thromboembolism study [17] reported that 36.7% of VTE patients had a GFR < 60 mL/min/1.73 m2 when it was estimated with CKD-EPI formula [18]. Although the prevalence varied from one study to another, it is undeniable that CKD is common in VTE patients. Moreover, other studies have shown that the relationship between CKD and VTE was in ‘‘both directions’’. Indeed, the Longitudinal investigation of thromboembolism etiology (LITE) study showed that among 19,073 patients followed
for 12 years, CKD was found to be a risk factor for VTE. In this study, annual incidences of VTE increased according to the renal function: 1.9 and 4.5 per 1000 patients among stage 2, and stage 3&4 CKD patients, respectively. The relative risk (RR) (adjusted for age, sex and race of the patients) of developing VTE was 2.1 with a 95% confidence interval (95% CI) of [1.5—3.0]. Moreover, this risk appeared early in the course of CKD, appearing for a GFR below 75 mL/min/1.73 m2 (estimated with the MDRD formula) [19]. Another study confirmed that the increased risk for VTE was beginning for a relatively high value of GFR. In this study, the risk appeared when the GFR reached 88 mL/min/1.73 m2 in a pooled analysis of 5 prospective studies that included 95,154 patients [20]. Furthermore, the hazard ratio (HR) for VTE was increasing with the decrease in GFR (estimated with CKD-EPI). Compared to normal renal function patients, CKD is a major risk factor for VTE, at a relatively early stage of renal disease, which only increases as the renal functions deteriorate. In addition, CKD is a risk factor for atherothrombosis [21], cardiovascular morbidity and mortality [22] and fatal pulmonary embolism (PE) in multivariate analysis [15]. CKD is also a risk factor of symptomatic PE and major bleeding [23]. In fact, CKD patients are at an increased risk of bleeding. Platelets can become dysfunctional, secondary to uremic related toxin exposure and can have further adhesion defects as a result of shear wall stress alterations during hemodialysis [6,24,25]. Blood loss and lower hemoglobin values can be a concern for dialysis efficiency in addition to providing adequate tissue oxygenation in a population prone to anemia. This may be most critical in comorbid conditions such as asthma or coronary artery disease [6]. It is therefore necessary to diagnose CKD and to monitor the progression of renal disease in order to optimize the management of these patients and to adjust their drug dosages, when necessary.
Prescriptions and ATHIR rules Prior to prescribing anticoagulant treatments such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs), a diagnosis needs to be made, followed by an assessment of the renal function (which will also be made during the treatment). When prescribing anticoagulant agents, a biological evaluation of the feasibility of starting the therapy in daily practice is possible with the ATHIR rule [26]: • A as anemia: full blood count, because anemia is a significant bleeding risk factor; • T as thrombocytopenia: platelet count, because an unknown thrombocytopenia is a haemorrhagic risk factor
Renal function and venous thromboembolic diseases and thrombocytosis is a risk factor for thrombosis; in some cases platelet monitoring is necessary; • H as haemostasis: quick test, prothrombin time and activated partial thromboplastin time are all informative parameters on haemostasis; • IR as insuffisance rénale (renal insufficiency): GFR according to an adequate formula. ATHIR rules are more common sense rules but if all these parameters are evaluated, anticoagulation therapy could be secure. These parameters also allow to detect bleeders [27]. From July to August 2014, the French Society of Vascular Medicine conducted a survey on this issue (188 answers). Eighty-eight percent of vascular medicine doctors prescribed an initial laboratory test at the initiation of an anticoagulant therapy. Overall, the rules of prescription were followed but some improvement is still possible. From a practical point of view, the prescription of anticoagulant agents must be done with reflection, according to the recommendations/good practices and with close communication with the patient.
Renal function The assessment of renal function has two objectives: one is clinical and the other is pharmacological. The clinical objective of this assessment is to estimate the risk of bleeding and the risk of recurrence VTE in patients treated with anticoagulants agents. The evaluation of renal function is historically carried out by using the Cockcroft-Gault formula (CG) [28]. Indeed, the literature data show a correlation between the result of the CG formula and the risk of: bleeding, fatal bleeding and fatal pulmonary embolism [12,15,23]. However, several studies have reported similar or better correlations when the assessment of renal function was performed with either the MDRD formula [29] or the CKD-EPI formula [18]. The second objective (pharmacological) is to evaluate the renal function in order to adjust the doses of all drugs and of anticoagulant agents in particular. Indeed, in CKD patients, it is necessary to adjust the dosage in order to avoid drug overdose secondary to the modification of the pharmacokinetic parameters of the drug. About half of available drugs in France today require a dose reduction in patients with CKD. For the remaining 50%, the drug must be given at its usual dose, even in cases of renal failure, to avoid inefficiency. It is therefore imperative to have access to reliable sources of information in order to determine the appropriate dose according to the CKD stage. This question is global and arises in all medical specialties and diseases. It has thus been shown that poor adaptation dosages have been associated with an increased mortality of about 25% in oncology [30,31], 16% in HIV infections [32], or 40% to 6 years in the elderly general French population [33]. The international Kidney disease: improving global outcomes (KDIGO) working group defined CKD in 2005 [3] and stated how to estimate the renal function for drug dosage adjustments in 2011 [34]. In both cases, it is stated that the method for estimating renal function should be as precise as possible and that, at the moment, the most accurate formula is the CKD-EPI. One important point to know is
391 that CKD-EPI and MDRD formulae show very similar performances when the GFR is lower than 60 mL/min/1.73 m2 and it is for this cut-off of GFR that the question of drug dosage adaptation is important. It is in fact rare that a drug requires a dosage adjustment when GFR is greater than 60 mL/min/1.73 m2 . Furthermore, the CG formula is inaccurate in elderly patients and in subjects with a body mass index greater than 25 or less than 18.5 [35,36]. In addition, the method for serum creatinine dosing has evolved several times since the development of the CG formula in 1976. Currently, laboratories use the Isotope dilution mass spectrophotometry (IDMS) method, which is more accurate than the method previously used. The CG formula has never been validated with these new techniques. The CKD-EPI and the MDRD formulas have been validated with the IDMS method. In addition, drug agencies and Scientific Societies have reported that the CG formula should be abandon for the estimation of the renal function (French Biomedicine Agency and French Nephrology Society [37], International Society of Geriatric Oncology [38], French National Health Authority [39]). For all these reasons, nephrologists are using the CKD-EPI formula (or at least the MDRD formula). However, because the CG formula was used in the clinical trial of most of anticoagulant agents, vascular physicians and cardiologists are using CG.
Low molecular weight heparins Low molecular weight heparins (LMWH) are a heterogeneous group of drugs. All LMWHs are composed of heparin chains of different lengths and weights. The relative composition between short and long chains varies from one drug to another [40]. Thus, enoxaparin has more short chains, excreted by the kidney, while tinzaparin has a majority of long chains, which are not eliminated by the kidney. This point is very important because short chains (enoxaparin) are eliminated by the renal glomerular filtration while long chains (tinzaparin) adhere to the surface of endothelial cells and are degraded in situ. However, LMWH are contra-indicated in CKD patients with severe renal impairment [41], which was one of the criteria of non-inclusion in the clinical trials. Several studies have investigated about the use of LMWH in CKD patients. It has been reported that LMWH with long chains (tinzaparin) did not accumulate at the prophylactic dosage of 4500 IU/day at day 1 and 8 in CKD patients unlike shorter chain LMWH (enoxaparin) used at the prophylactic dosage of 4000 IU/day [42] (Table 1). Furthermore, no tinzaparin accumulation was reported between day 2 and 5 in moderate and severe renal impairment patients with VTE in the IRIS study [43]. For curative VTE treatment, it was suggested to reduce the dosage of enoxaparin to reduce the bleeding risk observed in severe CKD patients [44].
Unfractionated heparin No modification of the pharmacokinetic of unfractionated heparin (UFH) was reported in CKD patients. Therefore, it can be used with the usual dosage in these patients, regardless of the level of renal function [45].
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Table 1 Pharmacokinetic parameters of tinzaparin/enoxaparin in CKD patients [42]. Paramètres pharmacocinétiques de la tinzaparine et de l’enoxaparine chez les patients insuffisants rénaux chroniques [42]. Tinzaparin Cmax , IU/mL (mean ± SD) Day 1 0.44 ± 0.16 Day 8 0.46 ± 0.19 P-value (Day 1 vs 8) > 0.05 AUC, IU/mL/min (mean ± SD) Day 1 252 ± 103 Day 8 273 ± 111 P-value (Day 1 vs 8) > 0.05 Trough level, IU/mL (mean ± SD) Day 1 0.05 ± 0.04 Day 8 0.06 ± 0.06 P-value (Day 1 vs 8) > 0.05
Enoxaparin 0.55 ± 0.14 0.67 ± 0.23 < 0.001 354 ± 119 447 ± 218 < 0.001 0.06 ± 0.06 0.11 ± 0.10 0.01
SD: standard deviation.
Vitamin K antagonist Data showed that the treatment with vitamin K antagonist (VKA) in CKD patients is neither easy nor standardized. There are no specific recommendations on the dosage adjustment of these drugs in CKD patients. VKA treatment for AF in patients with severe CKD has a poor safety and efficacy profile, likely related to suboptimal anticoagulation control. Furthermore, patients with severe CKD were at a high risk of stroke or transient ischemic attack and major bleeds during VKA treatment compared to those without CKD, HR = 2.75 (95% CI = 1.25—6.05) and HR = 1.66 (95% CI = 0.97—2.86), or with moderate CKD, HR = 3.93 (95% CI = 1.71—9.00) and HR = 1.86 (95% CI = 1.08—3.21), respectively [46]. Moreover, fluindione is nephrotoxic and several publications have reported that fluindione could induce acute interstitial nephritis [47,48]. Consequently, it is hard to use VKA in CKD patients and the use of these drugs expose the patient to higher risks of bleeding.
Direct oral anticoagulants DOACs are predominantly eliminated by the kidney. The frequency of renal excretion of the DOACs ranged from 59 to 85% according to the drug [49]. Modifications of the pharmacokinetic parameters of these drugs in CKD patients have been reported for the three DOACs available in France and it is necessary to adjust their dosage in CKD patients [41,50]. Clinical trials were conducted in CKD patients but patients with creatinine clearance < 30 mL/min were excluded from these studies [51—56]. The French National Drug Agency (Agence nationale pour la sécurité des médicaments [ANSM]) published a report in 2014 on the management of anticoagulants and recommended that these drugs be used with ‘‘great caution’’ and to reduce DOACs dosage but without any precise dosage. However, some recommendations from the Summary of product characteristics (SmPC) are available but not clearly applicable.
According to the SmPC of apixaban, a dose reduction is necessary in AF patients with CG between 15 and 30 mL/min. This conclusion seems awkward because the choice of apixaban dosage was not based on CG in the clinical trials but on creatininemia, age and weight (Amplify [56]; Amplify-EXT [57]; Averroes [52] and Aristotle [51,58]). In addition, there is a contradiction between the clinical trials and the SmPC that could lead to mistakes. For example, a 78-year-old man weighing 68 kg with a Scr = 218 mol/L should have received a full dose of apixaban in the clinical trial, according to the criteria; but, according to apixaban SmPC, this patient should receive a reduced dose in real life. Therefore, it is impossible to recommend a reduced/full dose of apixaban in CKD patients because the clinical trial methodology does not match with the apixaban SmPC recommendations. Chang et al. [59] performed a single dose pharmacokinetic study of apixaban (10 mg) in CKD patients. An increase of systemic exposure (from +27% to +77%) was reported and that the frequency of adverse events in patients with various degrees of CKD ranged from 29% to 42%, and was higher than that in subjects with normal renal function (13%). There were also a high variability in serum apixaban concentrations [60]. In addition, one study reported a pharmacokinetic study of apixaban performed in hemodialysis patients. The study showed an increase in systemic exposure (+36%) of apixaban after a single 5 mg dose [61]. The authors stated that ‘‘no dose adjustment is recommended in ESRD patients for any indication, with exception of non-valvular atrial fibrillation’’ and that in these patients ‘‘with ESRD and at least one the following characteristics: age ≥ 80 years, body weight ≤ 60 kg. It is recommended that apixaban dose be reduced from 5 mg twice daily to 2.5 mg twice daily’’. From a nephrological point of view, this statement is strange because hemodialysis patients have no renal function, regardless of their age and/or weight. Therefore, it is hard to recommend a dose on the basis of this study. The clinical trial of dabigatran randomized (CKD patients did not receive a specific experimental dose) patients into 2 different dose-groups (110 or 150 mg BID) of dabigatran in normal renal function patients and in CKD patients [62]. A pharmacokinetic simulation based on the data from the clinical trial of dabigatran was performed [63]. Based on the model, the authors reported that a dose of 75 mg BID could reach the target drug plasma concentration and that the exposure of the drug could be within the concentration range proved to be safe and effective. This dosing algorithm was also confirmed and supported by the FDA clinical pharmacology division but not by the European medicine agency. Among the 3 available DOACs, only the clinical development of rivaroxaban included one clinical trial with a dedicated dosage of rivaroxaban in a specific group of CKD patients with an estimation of the renal function [53]. Furthermore, several pharmacokinetic studies performed in hemodialysis patients reported that rivaroxaban was safe and efficient in these patients [64,65]. Finally, the clinical trials of the coming DOAC (edoxaban) included CKD patients for which a specific dosage was investigated [66,67]. Several others studies were performed and confirmed that edoxaban was safe and effective in CKD patients, including hemodialysis patients [68—71]. Consequently, it is necessary to reduce the doses of DOACs in CKD patients.
Renal function and venous thromboembolic diseases
Conclusion VTE is strongly associated to CKD. The main consequence of this association is a higher mortality in VTE patients with CKD than in patient without CKD. Therefore, it is important to screen and diagnose CKD in VTE patients using at least an adequate formula for the estimation of the glomerular filtration rate. CKD is not a ‘‘modifiable’’ risk factor, however its diagnosis could allow physicians to slow down the progression of the CKD by managing, for example, the known risk factors of CKD progression (such as diabetes, hypertension, nephrotoxic drug) and therefore, reduce the risk of VTE and the risk of death since it is correlated to the DFG.
Disclosure of interest Janus N: Leo Pharma, Pfizer, Vifor Pharma, Roche, Gilead, Daïchi-Sankyo, Guerbet, Amgen, Bayer, Pierre Fabre Oncologie. Launay-Vacher V: Amgen, Leo Pharma, Merck, Pierre Fabre Oncologie, Roche, Takeda, Teva, Bayer, BoehringerIngelheim, Hospira, Helsinn, Leo Pharma, Roche, Gilead, Daïchi-Sankyo, Guerbet. Avec le soutien institutionnel de Léo Pharma.
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